Normoprost

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NORMOPROST® (NORMOPROST®)

Composition:

Active substance: dutasteride;

1 capsule contains 0.5 mg of dutasteride;

Excipients: propylene glycol monocaprylate, butylhydroxytoluene (E 321);

capsule shell: gelatin, glycerin, titanium dioxide (E 171), medium-chain triglycerides and soy lecithin.

Pharmaceutical form. Soft capsules.

Main physicochemical characteristics: elongated soft gelatin capsules (approximately 16.5×6.5 mm) of light yellow color, filled with a clear liquid.

Pharmacotherapeutic group. Agents used in benign prostatic hyperplasia. Inhibitors of testosterone 5α-reductase.

ATC code G04C B02.

Pharmacological properties.

Pharmacodynamics.

Dutasteride is a dual inhibitor of 5α-reductase, inhibiting both type 1 and type 2 isoenzymes of 5α-reductase, which are responsible for the conversion of testosterone to 5α-dihydrotestosterone. Dihydrotestosterone is the androgen primarily responsible for the hyperplasia of prostate tissue. The maximum reduction in dihydrotestosterone during dutasteride treatment is dose-dependent and occurs within the first 1–2 weeks. After the first and second week of treatment with dutasteride at a daily dose of 0.5 mg, the mean serum concentration of dihydrotestosterone decreases by 85% and 90%, respectively.

In patients with benign prostatic hyperplasia (BPH) receiving 0.5 mg of dutasteride daily, the mean reduction in dihydrotestosterone levels was 94% after 1 year and 93% after 2 years of treatment. Mean serum testosterone levels increased by 19% both after 1 year and after 2 years of treatment.

Pharmacokinetics.

Dutasteride is administered orally in the form of soft gelatin capsules.

After administration of a single 0.5 mg dose, peak serum concentration of dutasteride is observed within 1–3 hours. Absolute bioavailability is 60%. Bioavailability is not affected by food intake.

Dutasteride has a large volume of distribution (300–500 L) after single or multiple doses. Protein binding exceeds 99.5%.

With daily administration of 0.5 mg, dutasteride serum concentration reaches 65% of steady-state concentration within 1 month and approximately 90% of this level by 3 months. A steady-state concentration of approximately 40 ng/mL in serum is achieved after 6 months of treatment with a daily dose of 0.5 mg. As in serum, steady-state concentration of dutasteride in semen is also reached after 6 months. After 52 weeks of treatment, the mean concentration of dutasteride in semen is 3.4 ng/mL (range: 0.4–14 ng/mL). The distribution ratio of dutasteride from serum to semen is approximately 11.5%.

In vitro, dutasteride is metabolized by human cytochrome P450 CYP3A4 enzymes into two monohydroxylated metabolites. Spectrometric analysis in human serum reveals unchanged dutasteride, three major metabolites (4´-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and two minor metabolites (6,4´-dihydroxydutasteride and 15-hydroxydutasteride).

Dutasteride is extensively metabolized. After oral administration of 0.5 mg/day, between 1% and 15.4% (mean 5.4%) of the administered dose is excreted in feces as unchanged dutasteride. The remainder of the dose is excreted as metabolites. Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are detected in human urine. The terminal elimination half-life of dutasteride is 3–5 weeks. Residual amounts of dutasteride in serum may be detected up to 4–6 months after discontinuation of treatment.

Based on pharmacokinetic and pharmacodynamic studies, dosage adjustment of dutasteride according to patient age is not required.

The effect of renal impairment on the pharmacokinetics of dutasteride has not been studied. However, less than 0.1% of the dose is excreted in human urine after administration of 0.5 mg of dutasteride; therefore, dosage adjustment in patients with renal impairment is not required.

The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied (see sections "Dosage and administration" and "Special precautions").

Clinical characteristics.

Indications.

Treatment of moderate to severe benign prostatic hyperplasia; reduction in the risk of acute urinary retention and the need for surgical intervention in patients with moderate to severe symptoms of benign prostatic hyperplasia.

Contraindications.

Contraindicated in patients with hypersensitivity to dutasteride, to other 5α-reductase inhibitors, soy, peanuts, or any other components of the drug.

Should not be used for the treatment of women and children (see section "Use during pregnancy or breastfeeding").

Contraindicated in patients with severe hepatic impairment.

Interactions with other medicinal products and other forms of interactions.

Information regarding reduction of PSA (Prostate-specific antigen) in blood serum during treatment with dutasteride, as well as information on detection of prostate cancer, see section "Special precautions for use".

Effect of other medicinal products on the pharmacokinetics of dutasteride

Use in combination with CYP3A4 and/or P-glycoprotein inhibitors

Dutasteride is primarily eliminated via metabolism. In vitro studies show that CYP3A4 and CYP3A5 are catalysts of its metabolism. Formal interaction studies with potent CYP3A4 inhibitors have not been conducted. However, in a population pharmacokinetic study, serum concentrations of dutasteride were on average 1.6–1.8 times higher in a small number of patients who were concurrently treated with verapamil or diltiazem (moderate CYP3A4 inhibitors and P-glycoprotein inhibitors) compared to other patients.

With long-term use of dutasteride in combination with medicinal products that are potent inhibitors of the CYP3A4 enzyme (e.g., ritonavir, indinavir, nefazodone, itraconazole, oral ketoconazole), serum concentrations of dutasteride may increase. Further inhibition of 5α-reductase due to prolonged action of dutasteride is unlikely. However, dose reduction of dutasteride may be considered if adverse effects develop.

It should be noted that in case of enzyme inhibition, the long half-life may become even longer, and concomitant therapy may thus need to continue for more than 6 months before a new steady-state concentration is achieved.

Administration of 12 g cholestyramine one hour after a single 5 mg dose of dutasteride did not affect the pharmacokinetics of dutasteride.

Effect of dutasteride on the pharmacokinetic characteristics of other medicinal products

Dutasteride does not affect the pharmacokinetics of warfarin or digoxin. This indicates that dutasteride does not inhibit/induce the activity of the CYP2C9 enzyme or the P-glycoprotein transporter. In vitro interaction studies data indicate that dutasteride does not inhibit the enzymes CYP1A2, CYP2D6, CYP2C9, CYP2C19, or CYP3A4.

In a small (N=24), two-week study involving healthy men, dutasteride (0.5 mg daily) did not affect the pharmacokinetics of tamsulosin or terazosin. No signs of pharmacodynamic interaction were observed in this study.

Special precautions for use.

Combined therapy may be prescribed only after careful assessment of benefit/risk due to the potential increased risk of adverse reactions (including heart failure) and after consideration of alternative treatment options, including monotherapy (see section "Dosage and administration").

Adverse reactions affecting the cardiovascular system

According to data from four-year clinical trials, the incidence of heart failure (a collective term for all reported events, primarily primary heart failure and congestive heart failure) was higher in patients treated with a combination of dutasteride and an alpha-blocker, mainly tamsulosin, compared to patients who did not receive such combination therapy. In these two trials, the incidence of heart failure was low (≤1%) and variable across the studies. There was no imbalance in the incidence of cardiovascular adverse events in any of the trials. A causal relationship between the use of dutasteride (alone or in combination with alpha-blockers) and the development of heart failure has not been established (see section "Pharmacological properties").

A meta-analysis of 12 randomized, placebo-controlled or comparative clinical trials (n = 18,802) was conducted to evaluate the risk of cardiovascular adverse events with dutasteride use (compared to the control group). There was no consistent statistically significant increase in the risk of heart failure (RR 1.05; 95% CI 0.71, 1.57), acute myocardial infarction (RR 1.00; 95% CI 0.77, 1.30), or stroke (RR 1.20; 95% CI 0.88, 1.64).

Effect on prostate-specific antigen (PSA)

Serum prostate-specific antigen (PSA) level is an important component of the screening process for detecting prostate cancer.

Dutasteride can reduce serum PSA levels by approximately 50% on average within 6 months of treatment.

Patients taking dutasteride should establish a new baseline PSA level 6 months after starting treatment with this medication. This level should then be monitored regularly. Any confirmed increase in PSA from the lowest level during dutasteride treatment may indicate the presence of prostate cancer or non-compliance with dutasteride therapy and requires careful evaluation, even if PSA levels remain within the normal range for men not treated with 5α-reductase inhibitors. When interpreting PSA levels in patients receiving dutasteride, previous PSA values should be considered for comparison.

The use of dutasteride does not affect the utility of PSA levels for diagnosing prostate cancer after establishing a new baseline level.

Total serum PSA returns to baseline levels within 6 months after discontinuation of treatment.

The ratio of free PSA to total PSA remains constant even during dutasteride treatment. Therefore, if a physician decides to use the percentage of free PSA as a diagnostic tool for prostate cancer in a patient taking dutasteride, no adjustment of the value is necessary.

Digital rectal examination, as well as other methods for detecting prostate cancer, should be performed before starting dutasteride treatment and periodically during therapy.

Prostate cancer and high-grade tumors (poorly differentiated) according to Gleason score

In a four-year clinical trial involving >8000 men aged 50 to 75 years with prior negative prostate biopsy for prostate cancer and initial PSA levels between 2.5 ng/mL and 10.0 ng/mL (the REDUCE study), prostate cancer was diagnosed in 1517 patients. The incidence of high-grade prostate cancer (Gleason score 8–10) was higher in the group treated with dutasteride (n=29, 0.9%) compared to the placebo group (n=19, 0.6%). No increase in the incidence of prostate cancer with Gleason scores 5–6 or 7–10 was observed. A causal relationship between dutasteride use and high-grade prostate cancer has not been established. The clinical significance of this numerical imbalance is unknown. Men receiving dutasteride should be regularly monitored for the risk of prostate cancer, including PSA testing.

In an additional two-year follow-up study of patients who participated in the dutasteride chemoprevention trial (the REDUCE study), the incidence of new prostate cancer cases was low (dutasteride group [n=14, 1.2%] vs. placebo group [n=7, 0.7%]), with no new cases of Gleason 8–10 prostate cancer identified.

Long-term follow-up (up to 18 years) of patients from a clinical trial using another 5α-reductase inhibitor (finasteride) for chemoprevention showed no statistically significant difference between the finasteride and placebo groups in overall survival (HR 1.02, 95% CI 0.97–1.08) or survival after diagnosis of prostate cancer (HR 1.01, 95% CI 0.85–1.20).

Breast cancer

Rare cases of male breast cancer have been reported during clinical trials and in the post-marketing period. However, epidemiological studies indicate no increased risk of male breast cancer with 5α-reductase inhibitors. Patients should promptly report any changes in breast tissue, such as nipple discharge or swelling.

Damaged capsules

Dutasteride is absorbed through the skin; therefore, women and children should avoid contact with damaged capsules. If capsule contents come into contact with the skin, the area should be washed immediately with soap and water.

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied. Due to the extensive metabolism of dutasteride and its long elimination half-life (3–5 weeks), caution should be exercised when treating patients with mild to moderate hepatic impairment (see sections "Dosage and administration", "Contraindications", "Pharmacological properties").

This medicinal product contains soy lecithin, which may contain soybean oil. Do not take this medicine if you are allergic to peanuts and/or soy.

Use during pregnancy or breastfeeding.

Dutasteride is contraindicated for use in women.

Use during pregnancy

Like other 5α-reductase inhibitors, dutasteride inhibits the conversion of testosterone to dihydrotestosterone, which may impair the development of external genitalia in male fetuses. A small amount of dutasteride has been detected in the semen of subjects taking 0.5 mg of dutasteride daily. It is unknown whether dutasteride transferred to a woman via semen from a man being treated with dutasteride affects a male fetus (this risk is highest during the first 16 weeks of pregnancy).

As with other 5α-reductase inhibitors, it is recommended that patients use condoms if their partner is pregnant or potentially could become pregnant, to prevent semen exposure to the woman.

Use during breastfeeding

It is unknown whether dutasteride passes into breast milk.

Fertility

Cases of effects of dutasteride on semen characteristics (reduced sperm count, ejaculate volume, and sperm motility) have been reported in healthy men. A risk of reduced male fertility cannot be excluded.

Ability to influence the reaction rate when driving or operating machinery.

Due to the pharmacokinetic and pharmacodynamic properties of dutasteride, it does not affect the ability to drive or operate machinery.

Dosage and Administration

Dutasteride may be prescribed as monotherapy or in combination with the alpha-1-adrenergic blocker tamsulosin (0.4 mg).

Adults (including elderly patients)

The recommended dose of dutasteride is 1 capsule (0.5 mg) once daily, taken orally. The capsule should be swallowed whole and not opened or chewed, as contact with the capsule contents may cause irritation of the oral and pharyngeal mucosa.

Dutasteride may be taken regardless of food intake.

Although symptom improvement may be observed early during treatment, treatment should be continued for at least 6 months to allow an objective assessment of the drug's efficacy.

Renal impairment

The pharmacokinetics of dutasteride have not been studied in patients with renal impairment; therefore, caution should be exercised when prescribing to patients with severe renal impairment.

Hepatic impairment

The pharmacokinetics of dutasteride have not been studied in patients with hepatic impairment; therefore, the drug should be used with caution in patients with mild to moderate hepatic impairment. Dutasteride is contraindicated in patients with severe hepatic impairment.

Children

Use in children is contraindicated.

Overdose

Clinical studies have shown that single doses of dutasteride up to 40 mg/day (80 times higher than therapeutic doses) administered for 7 days did not raise safety concerns in healthy volunteers. During clinical trials, doses of dutasteride up to 5 mg/day for 6 months were administered without additional adverse reactions compared to the standard dose of 0.5 mg/day.

There is no specific antidote; therefore, in the event of a potential overdose, symptomatic and supportive therapy should be administered.

Adverse reactions.

Monotherapy with dutasteride

Adverse reactions occurred in approximately 19% of 2167 patients treated with dutasteride during the first year of treatment in 2-year placebo-controlled Phase III studies. Most of the observed adverse events were mild or moderate in severity and involved the reproductive system. During the subsequent 2 years in open-label extension studies, no changes in the adverse event profile were observed.

Table 1 lists the adverse reactions identified during controlled clinical trials and in the post-marketing period. The adverse events listed below, observed during clinical trials and considered by investigators to be drug-related (with a frequency ≥1%), occurred more frequently in patients receiving dutasteride compared to placebo during the first year of treatment. Adverse events reported during the post-marketing period were identified from spontaneous post-marketing reports, therefore their actual frequency is unknown.

Frequency classification: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

Table 1.

* Adverse reactions related to sexual function disturbances are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after discontinuation of treatment. The effect of dutasteride on their duration is unknown.

^ includes decreased semen volume.

• includes breast tenderness and breast enlargement.

Dutasteride in combination with the alpha-blocker tamsulosin

Data from the 4-year CombAT study, which compared daily administration of dutasteride 0.5 mg (n = 1,623) and tamsulosin 0.4 mg (n = 1,611) alone and in combination (n = 1,610), showed that the incidence of drug-related adverse events during the first, second, third, and fourth year of treatment was 22%, 6%, 4%, and 2% for combination therapy with dutasteride/tamsulosin, 15%, 6%, 3%, and 2% for dutasteride monotherapy, and 13%, 5%, 2%, and 2% for tamsulosin monotherapy, respectively. The higher incidence of adverse reactions in the combination therapy group during the first year of treatment was due to a higher frequency of reproductive system disorders, particularly ejaculation disorders observed in this group.

During the first year of treatment in the CombAT study, the adverse reactions listed below, considered by investigators to be related to drug administration, were reported at a frequency of ≥1%; the incidence of these reactions over four years of treatment is presented in Table 2.

Table 2.

a Combination: dutasteride 0.5 mg once daily plus tamsulosin 0.4 mg once daily.

b The general term "Heart failure" includes congestive heart failure, heart failure, left ventricular failure, acute heart failure, cardiogenic shock, acute left ventricular failure, right ventricular failure, acute right ventricular failure, ventricular failure, cardiopulmonary failure, and congestive cardiomyopathy.

c The adverse reactions related to the reproductive system listed below are associated with the use of dutasteride (including monotherapy and combination with tamsulosin). The listed adverse reactions may persist after discontinuation of treatment. The role of dutasteride in this persistence is unknown.

d Includes breast tenderness and breast enlargement.

^ Includes decreased semen volume.

Other data

The REDUCE trial revealed a higher incidence of prostate cancer with Gleason score 8–10 in men receiving dutasteride compared to placebo. It is unknown whether the results of this trial were influenced by prostate volume reduction or other factors related to dutasteride use.

During clinical trials and post-marketing surveillance, cases of male breast cancer have been reported (see section "Special precautions").

Reporting of adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: http://aisf.dec.gov.ua.

Shelf life.

3 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging to protect from light.

Keep out of reach and sight of children.

Packaging.

15 capsules in a blister pack, 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ALKALOID AD Skopje /
ALKALOID AD Skopje.

Manufacturer's address and location of its business operations.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia /
Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.